It is becoming clear that periodontitis is not only characterized by pathogenic infection, but even more so by a loss of immunological homeostasis. Strategies toward resolution of regenerating the periodontium without completely blocking immune responses against local and systemic infections would be ideal. Our long-term objective is to address the physiological cause of periodontitis through an understanding of the inflammatory and regulatory processes of the periodontium. Correspondingly, recent data in our laboratories indicate that periodontitis symptoms are accompanied by the absence of an important cell subset called regulatory T- cells. We hypothesize that controlled release formulations of Treg-recruiting factors is a viable way to both regenerate the periodontal space and regenerate lost bone. This hypothesis is supported by our preliminary data demonstrating that controlled release of Treg recruiting factors leads to an increase in regulatory T-cells in the periodontium and resolution of periodontal disease symptoms in mice. Specific Aim I: To engineer controlled release formulations that allow us to explore both combinations of regulatory T-cell chemokines and also different temporal release profiles of these chemokines. We will rationally design formulations that release various regulatory T-cell chemoattractants differently over time. Specifically, we will compare our current formulations that release contents linearly over time with those that burst a larger amount of chemokine initially, followed by either linear release or another subsequent burst. Specific Aim II: Mechanistic analysis of host response to Treg recruiting formulation and its effect on periodontal regeneration. In this aim, we will: A) examine the mechanisms of regulatory T-cell migration to periodontal space and resolution of periodontal disease;and B) examine if Treg recruiting formulations induce periodontal regeneration. We will use chemokine receptor and suppressive cytokine knock-out mice in order to accomplish the former. We will utilize a specific osteogenesis quantitative chip PCR assay and protein expression analysis to accomplish the latter. Such information would lead to more direct, and efficient, therapies in the future.